Phosphatase and Tensin Homolog or PTEN is a tumor suppressor gene. It is also known as mutated in multiple advanced cancer 1 (MMAC1). It is one of the most commonly mutated of all tumour suppressor genes, and if not mutated, it is often suppressed or downregulated. Somatic PTEN mutations and deletions, and inactivation of PTEN by methylation or microRNA silencing, are common in multiple tumour types. PTEN hamartoma tumour syndrome (PHTS) is a group of syndromes characterized by benign growths and a high risk for cancers of the breast, endometrium and thyroid. Cowden syndrome is the best characterized of these and 85% of patients have germline PTEN mutations. The range of abnormalities in patients with PHTS varies from patient to patient. Tumors associated with alteration of PTEN gene include the classical PHTS-associated tumours like breast, endometrium and thyroid, and also tumours of the central nervous system, prostate, lung, pancreas, liver and adrenal glands, as well as melanoma, leukaemia and lymphoma. An analysis of PTEN gene alteration in different cancer from COSMIC website is below:
Primary tissue% MutatedCentral nervous system50Endometrium40Prostate40Skin25Testis25Biliary tract20Urinary tract16.67Breast16.28Kidney14.29Ovary13.64Haematopoietic and lymphoid tissue11.9Soft tissue11.11Lung9.21Thyroid9.09Bone8.82Cervix7.69Stomach4.76Upper aerodigestive tract4.55Autonomic ganglia3.03Large intestine2.63
PTEN is a phosphatase and its lipid phosphatase activity dephosphorylates the 3-phosphoinositide products of PI3K. 3-phosphoinositides can activate important survival kinases, such as phosphoinositide-dependent kinase 1 (PDK1; encoded by PDPK1) and AKT. Change in the phosphatase activity or deletion/downregulation of PTEN gene will result in hyper-activated AKT signalling. Other aberrations as in PI3K gene can also mimic the PTEN effect resulting in high AKT signaling. This hyper-activated AKT signalling will affect different processes such as cell cycle progression, metabolism, migration, apoptosis, transcription and translation. Highly activated AKT also confers resistance to different chemotherapy. PTEN mutation is also associated with the resistance to different targeted therapies, for example PTEN is associated with resistance to anti-HER2 therapy and anti-EGFR therapy in Breast cancer and Colorectal cancer respectively. PTEN mutated cells have also been shown to give resistance to MEK inhibitors in KRAS mutated cells.
Though preclinical studies have shown that mTOR inhibitors as single agents have shown preclinical success in PTEN mutated profiles, in clinical trial these inhibitors have shown limited efficacy and evidences are less of PTEN mutation and mTOR inhibitor sensitivity
(Fleming et. al. “Phase II trial of temsirolimus in patients with metastatic breast cancer”. Breast Cancer ResTreat. 2012 November; 136(2):355-63. doi: 10.1007/s10549-011-1910-7. Epub 2012 Jan. 13. PMID: 22245973).
In addition to aberrations in PTEN gene, TP53 is another tumor suppressor gene that is widely known to be deleted or mutated or inactivated in a large percentage of all cancers. Presence of TP53 gene aberration in a cancer is related to a bad prognosis and greater severity of the disease with minimal treatment options available.
Thus, as observed above, the existing standard of care does not work on a large section of patients harboring mutations in PTEN and P53 gene. Even chemotherapy has not been found to be effective on these tumors. Single agent therapies have been used as therapies or suggested for use as therapies for cancer treatment for the purpose of improving one or more undesirable symptoms associated with the disease states or for slowing the progression (worsening) of the symptoms. However, the success achieved with the single agents has been limited and hence improved treatment protocols for this complex and devastating disorder especially in the subset of tumors harboring these mutations, are greatly needed. A safe and effective treatment that could alleviate suffering and improve outcomes would be a significant medical advance for cancer treatment and potentially for the treatment of other end-stage diseases as well.
The present invention addresses the drawbacks of existing therapies by providing a composition and a method of treatment of such cancers using the composition.